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WO1995032203A2 - Utilisation de derives de tetrahydropteridine comme inhibiteurs de la no-synthase - Google Patents

Utilisation de derives de tetrahydropteridine comme inhibiteurs de la no-synthase Download PDF

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Publication number
WO1995032203A2
WO1995032203A2 PCT/EP1995/001785 EP9501785W WO9532203A2 WO 1995032203 A2 WO1995032203 A2 WO 1995032203A2 EP 9501785 W EP9501785 W EP 9501785W WO 9532203 A2 WO9532203 A2 WO 9532203A2
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Prior art keywords
hydrogen
methyl
radical
phenyl
alkyl
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English (en)
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WO1995032203A3 (fr
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Wolfgang Pfleiderer
Harald Schmidt
Rainer Henning
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Hoechst AG
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Hoechst AG
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Priority to EP95921745A priority Critical patent/EP0760818B1/fr
Priority to JP53002295A priority patent/JP4287506B2/ja
Priority to DE59510094T priority patent/DE59510094D1/de
Priority to AT95921745T priority patent/ATE214068T1/de
Priority to CA002188267A priority patent/CA2188267C/fr
Publication of WO1995032203A2 publication Critical patent/WO1995032203A2/fr
Publication of WO1995032203A3 publication Critical patent/WO1995032203A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the present invention relates to pteridine derivatives of the general formula I,
  • Nitric oxide plays an important role in a wide variety of physiological processes (see, for example, R. Henning, Nachr. Che. Tech. Lab. 41 (1993), 413; HHHW Schmidt Schmidt et al., Biochim. Biophys. Acta 1178 (1993 ), 153).
  • NO also acts as a messenger in the NANC nerves of the peripheral nervous system.
  • the cell-toxic effect of NO is used by macrophages for the defense against infection.
  • Endogenous NO is formed from arginine using at least three different NO synthase isoenzymes (see, for example, JFKerwin, Jr., M. Heller, Med. Res. Rev. 14 (1994), 23).
  • the constitutive, calcium-dependent NO synthases are found, for example, in endothelium (type III) and in the brain (type I), where they are involved in the regulation of blood pressure and coagulation or in conduction processes.
  • the cytokine-inducible, calcium-independent isoform (type II) occurs in macrophages, smooth muscle cells and and hepatocytes. It is able to produce relatively large amounts of NO over a long period of time and is made responsible for inflammatory processes and the cell-toxic activity of the macrophages.
  • a disturbed NO household leads to serious illnesses and injuries.
  • the excessive formation of NO in septic or hemorrhagic shock leads to massive pathological drops in blood pressure.
  • Excessive NO production is involved in the development of type 1 diabetes and atherosclerosis and also appears to be responsible for the glutamate-induced neurotoxicity after cerebral ischemia.
  • High NO concentrations can moreover lead to DNA damage through deamination of cytosine.
  • diseases which are caused indirectly or directly by a lack of endogenous NO are arterial hypertension, disorders of the hemostasis, coronary heart disease and erectile dysfunction.
  • EP-B-108 890 relates to the use of pteridine derivatives for the treatment of diseases due to a catechola deficiency, such as Parkinson's disease, and the use of pteridines for the treatment of phenylketonemia (see also ECBigham et al., Chemistry and Biology of Pteridines (1986), S.lll, Walter de Gruyter & Co., Berlin, New York); this also includes certain compounds of the general formula I in which X stands for oxygen and R 1 , R, R 3 and R 7 simultaneously stand for hydrogen.
  • the present invention relates to the use of pteridine derivatives of the general formula I
  • X represents 0 or NH;
  • R represents hydrogen, methyl, (C ⁇ -C ⁇ ) alkanoyl, nicotinoyl or (l-methyl-3-pyridinio) carbonyl;
  • R represents hydrogen or methyl;
  • R 3 for hydrogen, methyl, ethyl, benzyl, -C ⁇ C $ ) alkanoyl, unsubstituted benzoyl, substituted benzoyl, pyridoyl, thienylcarbonyl, one of the radicals
  • R 9 R 9a is N-C0-, the radical R 9 R 9a is N-CS-, phenoxycarbonyl or benzyloxycarbonyl; R is hydrogen, (C2-C5) -alkyl, unsubstituted
  • R 4a for hydrogen, (C 1 -C 4 ) alkylmercapto, the rest
  • m represents the numbers 1 or 2
  • the radical -NR 11 R 12 or the radical -OR 13 or R J and R ⁇ ⁇ together represent the grouping -CO-O-, the carbonyl carbon atom of which is bonded to the 5-position of the pteridine molecule
  • R 5 represents hydrogen, methyl or phenyl
  • R 6 represents hydrogen or methyl
  • R represents hydrogen or methyl
  • R 8 represents (C ⁇ C ⁇ ) alkyl or benzyl
  • R J represents hydrogen, (C ⁇ Cg) alkyl, cyclohexyl, phenyl or benzoyl;
  • R 9a represents hydrogen, methyl or ethyl;
  • R 10 represents methyl;
  • R ⁇ J - and R AA independently represent hydrogen or methyl;
  • R 13 is hydrogen, (CJ-C Q ) alkyl, 2-methoxyethyl,
  • Alkyl groups can be straight-chain or branched. This also applies if they occur in other groups, for example in alkoxy, alkylmercapto, alkoxycarbonyl or alkanoyl groups. Examples of alkyl groups which are present in the compounds of the general formula to be used according to the invention as such, that is to say as (C 1 -C 4 ) -, (C2-C5) -, ( c l ⁇ c 6) ⁇ or (-C-C ⁇ o ) - A lky.
  • ' or can occur in other groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 3-methylbutyl, 2,2 -Dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
  • Examples especially for (C 1 -C 5 ) alkanoyl are formyl, acetyl, propionyl, n-butyryl, i-butyryl, n-valeroyl, 3-methyl-n-butyryl or 2,2-dimethylpropionyl.
  • Examples of (C 1 -C 2 ) alkoxy are methoxy and ethoxy.
  • Examples of unsubstituted or substituted in the alkyl part by a phenyl radical are 2-amino- (C2 ⁇ C) -alkanoyl are the corresponding residues of the amino acids glycine, alanine, valine, leucine, isoleucine, norvaline, norleucine, phenylglycine or phenylalanine.
  • Substituted phenyl groups and benzyl groups can be substituted one or more times, they are preferably one to three times substituted.
  • the substituents can be in any position, for example a single substituent in the ortho, eta or para position. In the case of multiple substitution, the substituents can be the same or different. Suitable substituents can be present spiellois C ⁇ - ⁇ ) - alkyl, (C ⁇ -C 4) -alkoxy, amino, (C 1 -C 4) alkylamino, di ((C 1 -C 4) alkyl) amino, Nitro or halogen, where only up to two nitro groups can be present. Halogen is, for example, fluorine, chlorine, bromine or iodine.
  • Thienylcarbonyl can Be 2- or 3-thienylcarbonyl.
  • acids of the formula HA are hydrogen chloride
  • a ⁇ can also stand for an anion of another inorganic or organic acid which is suitable from a pharmacological and pharmaceutical aspect and, if the compound of the general formula I is in the form of an acid addition salt, with the anion introduced by this salt formation match or differ.
  • the compounds of the general formula I can exist in various tautomeric forms and in various stereoisomeric forms.
  • the present invention includes not only the use of all tautomeric forms, but also all stereoisomeric forms, e.g. those of pure enantiomers, of enantiomer mixtures and racemates, of pure diastereomers and diastereomer mixtures or of cis / trans isomers.
  • X preferably represents oxygen.
  • R x and R ⁇ are preferably simultaneously hydrogen or simultaneously methyl, or R -6 is hydrogen and R 1 is simultaneously in particular acetyl, i-butyryl or pivaloyl, or for nicotinoyl or (l-methyl-3-pyridinio) carbonyl.
  • R x and R ⁇ are preferably simultaneously hydrogen or simultaneously methyl, or R -6 is hydrogen and R 1 is simultaneously in particular acetyl, i-butyryl or pivaloyl, or for nicotinoyl or (l-methyl-3-pyridinio) carbonyl.
  • R A and R ′′ simultaneously represent hydrogen or R for hydrogen and at the same time R for i-butyryl.
  • R J preferably represents hydrogen or an acyl radical or a (thio) carbamoyl radical.
  • acyl radicals preference is given to (C ⁇ C ⁇ ) alkanoyl, in particular formyl, acetyl and pivaloyl, unsubstituted or mono-, di- or trisubstituted benzoyl, thienylcarbonyl, and nicotinoyl and the radicals
  • R 8 is preferably methyl, n-octyl or benzyl and preferred substituents in substituted benzoyl groups are halogen and methoxy.
  • R 9 R 9a N-CO- R 9 preferably represents hydrogen, C 1-4 alkyl, in particular tert-butyl, and also cyclohexyl and phenyl and at the same time R 9a represents hydrogen, or it R 9 and R 9a simultaneously represent methyl.
  • R 9 preferably represents hydrogen, (C - ⁇ - ⁇ ) - alkyl, in particular methyl and ethyl, and also phenyl and benzoyl and at the same time R 9a represents hydrogen.
  • R J particularly preferably represents hydrogen, the N-phenylthiocarbamoyl radical, the unsubstituted benzoyl radical, the nicotinoyl radical or a 3-pyridinocarbonyl radical derived from the latter by alkylation or benzylation on the nicotinoyl nitrogen or one alkylated in the 1-position of the pyridine ring or benzylated 1,4-dihydro-3-pyridylcarbonyl.
  • R 4 preferably represents hydrogen, phenyl, phenyl substituted by an acetylamino group, in particular phenyl substituted by a para-standing acetylamino group, or the radical R 4a -CH 2 -.
  • R 4a preferably represents hydrogen or the radical -OR 3 . If R 4 is hydrogen or R 4a is hydrogen, it is particularly preferred if R 3 is simultaneously an acyl radical or a (thio) carbamoyl radical.
  • R 5 preferably represents hydrogen.
  • R preferably represents hydrogen
  • R 9a preferably represents hydrogen.
  • R 13 preferably represents hydrogen, or an acyl radical, in particular (C ⁇ -C ⁇ J-alkanoyl or unsub ⁇ stitusammlungs or in the alkyl moiety by a phenyl radical sub- stituêts 2-amino- (C2-Cg) alkanoyl. More preferably R 13 is (C j -C T ⁇ J-alkyl or (C 1 -C 5 ) alkanoyl, especially acetyl. If R 13 stands for C 1 -C 1 Q ) alkyl, then n-alkyl radicals as well as i-propyl, i-butyl and tert -Butyl preferred.
  • X represents 0 or NH
  • R 1 represents hydrogen, methyl, (C 1 -C 5 ) alkanoyl, nicotinoyl or (l-methyl-3-pyridinio) carbonyl;
  • R ⁇ represents hydrogen or methyl;
  • R 3 for hydrogen, methyl, ethyl, benzyl, (C ⁇ -C ⁇ ) - alkanoyl, benzoyl, nicotinoyl, one of the residues
  • radical R 9 is NH-CO-, the radical R 9 is NH-CS- or benzyloxycarbonyl;
  • Radical -NR 11 R 12 or the radical -OR 13 or R and R together represent the grouping -CO-O-, their carbonyl carbon atom being at the 5-position of the
  • R 5 and R 5 are independently hydrogen or
  • R represents hydrogen or methyl
  • R 8 represents (C 1 -C 1Q ) alkyl or benzyl
  • R 9 represents hydrogen, C ⁇ -C Q) alkyl, cyclohexyl, phenyl or benzoyl;
  • R 10 represents methyl
  • R and R independently of one another for hydrogen or
  • R 13 for hydrogen, 2-methoxyethyl, Phenyl, 3-phenylpropyl, 3-cyclohexylpropyl, (C - ⁇ -,) - alkanoyl, hydroxyacetyl, unsubstituted or substituted in the alkyl part by a phenyl radical 2-amino- (C 2 -Cg) -alkanoyl or ((C 1 -C2) -Alkoxy) carbonyl;
  • A. ⁇ ⁇ represents a pharmacologically acceptable anion; and their tautomeric forms and their pharmacologically acceptable salts for the prevention and treatment of diseases which are caused by an increased nitrogen monoxide level.
  • Particularly preferred compounds of the general formula I to be used according to the invention are those in which R 1 , R, R 3 , R 5 , R ° and R 7 simultaneously represent hydrogen and R 4 represents the radical R 4a -CH 2 ⁇ is and therein R is an amino group, a methylamino group, a dimethylamino group, a or an acetoxy group. Also particularly preferred to be used are those in which R, R, R, R ° and R 7 are simultaneously hydrogen, R1 is hydrogen or isobutyryl and R 3 is an acyl radical or a (thio) carbamoyl radical .
  • Another group of compounds of the general formula I to be used with particular preference are those in which R, R D and
  • R 1 - stands for hydrogen or isobutyryl
  • R J stands for an acyl radical
  • R 4 stands for phenyl or through an acetylamino group, in particular a para-standing acetylamino group, substituted phenyl
  • R 5 represents hydrogen or phenyl.
  • the compounds of the general formula I are known and can be prepared by or analogously to known processes.
  • Known synthesis methods for pteridine derivatives of the general formula I are, for example, the method by Gabriel-Isay or the Taylor method (see e.g.
  • the compounds of general formula I to be used according to the invention can form salts with inorganic or organic acids.
  • Suitable acids for the formation of pharmacologically acceptable acid addition salts are, for example: hydrogen chloride, hydrogen bromide, naphthalenedisulfonic acids, in particular naphthalenedisulfonic acid (1.5), phosphoric, nitric, sulfuric, oxalic, milk, wine, vinegar, salicyl , Benzoin, ants, propion, pivaline, diethyl vinegar, malon, amber, pimelin, fumar, malein, apple, sulfamine, phenylpropion, glucon, ascorbin, Isonicotinic, methanesulfonic, p-toluenesulfonic, citric or adipic acid.
  • the compounds of the general formula I can add one or more, for example two or three, in particular two, acid equivalents.
  • the acid addition salts can be prepared as usual by combining the components, advantageously in a suitable solvent or diluent. Acid addition salts can be converted into one another by anion exchange. A ⁇ can also represent an anion of one of the acids mentioned.
  • Compounds of the general formula I which contain acidic groups can form salts with inorganic or organic bases. Examples of such salts are, for example, alkali metal salts, in particular sodium and potassium salts, or ammonium salts, in particular those with organic radicals on the ammonium nitrogen.
  • the inhibition of NO release by the compounds of general formula I can be determined by an activity assay, which is based on work by Bredt and Snyder and Schmidt et al. based (see DSBredt and SS
  • Enzyme incubation removes L-citrulline from unused L-arginine by means of ion exchange chromatography from the reaction mixture; the 3 H activity determined by liquid scintillation measurement then corresponds to the amount of L-citrulline. Details of the implementation are given below.
  • Diseases which arise from an increased NO level and which can thus be treated according to the invention with the compounds of the general formula I or which can be prevented with them are, in particular, pathological drops in blood pressure such as those seen in septic or hemorrhagic conditions Shock that occurs with tumor or cancer therapy with cytokines or with liver cirrhosis.
  • pathological drops in blood pressure such as those seen in septic or hemorrhagic conditions Shock that occurs with tumor or cancer therapy with cytokines or with liver cirrhosis.
  • inflammatory diseases such as rheumatoid arthritis and in particular ulcerative colitis, as well as insulin-dependent diabetes mellitus and transplant rejection reactions.
  • arteriosclerosis In the cardiovascular area, these are arteriosclerosis, post-ischemic tissue damage and infarct damage, reperfusion damage, myocarditis based on a Coxsackie virus infection and cardiomyopathy; in the area of the nervous system / central nervous system, neuritides of different etiogenesis (forms of neuritis), encephalomyelitids, viral neurodegenerative diseases, Alzheimer's disease, hyperalgesia, epilepsy and migraines; in the kidney area acute kidney failure as well as nephritis of different etiogenesis, especially glomerulonephritis.
  • the compounds of the general formula I and their pharmacologically acceptable salts can be used as auxiliaries in biochemical and pharmacological studies in research and in diagnostic processes, and they can be used in animals, preferably in mammals, and in particular in humans, as a remedy in themselves alone, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as an active ingredient, contain an effective dose of at least one compound of the general formula I or a salt thereof, in addition to conventional pharmaceutically acceptable carriers - and additives.
  • the remedies can be taken orally, for example in the form of pills, tablets, lacquer tablets, coated tablets, hard and soft gelatine. capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures.
  • administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions or infusion solutions, or percutaneously, for example in the form of ointments or tinctures.
  • the pharmaceutical preparations can also contain additives such as Fillers, extenders, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, taste or flavoring agents, buffer substances, furthermore solvents or solubilizers or Means to achieve a depot effect, as well as salts to change the osmotic pressure, coating agents or
  • antioxidants Contain antioxidants. They can also contain two or more compounds of the general formula I or their pharmacologically acceptable salts and still other therapeutically active substances.
  • Such other therapeutically active substances are, for example: ⁇ -receptor blockers, such as e.g. Propanolol, pindolol, metoprolol; Vasodilators, e.g. Carbocromes; Sedatives, e.g. Barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; Diuretics, such as Chlorothiazide; heart tonifying agents such as Digitalis preparations; antihypertensive agents such as Hydralazine, dihydralazine, ramipril, prazosin, clonidine, rauwolfia alkaloids; Agents that lower the level of fatty acids in the blood, e.g. Bezafibrate, fenofibrate;
  • Agents for thromboprophylaxis such as phenprocoumon; anti-inflammatory substances such as corticosteroids, salicylates or propionic acid derivatives such as ibuprofen; Antibiotics such as penicillins or cephalosporins; NO donors, such as organic Nitrates or Sydnonimine or Furoxane.
  • the dosage can vary within wide limits and must be adapted to the individual circumstances in each individual case.
  • the daily dose is in similar quantitative ranges, i.e. generally also at 0.5 to 100 mg / person.
  • the daily dose can be divided into several, e.g. 2 to 4, partial administrations can be divided.
  • Pharmaceutically inert inorganic or organic carriers can be used to produce the pharmaceutical preparations.
  • Carriers for soft gelatin capsules and suppositories are e.g. Fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
  • Suitable carriers for the production of solutions and syrups are e.g. Water, sucrose, invert sugar, glucose, polyols etc.
  • Suitable carriers for the production of injection solutions are e.g. Water, alcohols, glycerin, polyols or vegetable oils.
  • the present invention provides the first medical indication for such compounds.
  • the present invention also relates to pteridine derivatives of the general formula I, in the
  • X represents O or NH
  • R 1 for hydrogen, methyl, Nicotinoyl or (1-methyl-3-pyridinio) carbonyl
  • R ⁇ represents hydrogen or methyl
  • R J for hydrogen, methyl, ethyl, benzyl, (C -C 5 ) alkanoyl, unsubstituted benzoyl, substituted benzoyl, pyridoyl, thienylcarbonyl, one of the residues
  • R 9 R 9a is N-CO-, the radical R 9 R 9a is N-CS-, phenoxycarbonyl or benzyloxycarbonyl; R is hydrogen, (C2-C5) alkyl, unsubstituted
  • Phenyl substituted phenyl or the radical R -er ⁇ ; R 4a for hydrogen, (C 1 -C 4 ) alkylmercapto, the rest
  • R 5 represents hydrogen, methyl or phenyl
  • R ° represents hydrogen or methyl
  • R 7 represents hydrogen or methyl
  • R 8 for or benzyl
  • R 9 represents hydrogen, (C 1 -Cg) alkyl, cyclohexyl, phenyl or benzoyl
  • R represents hydrogen, methyl or ethyl
  • R 10 represents methyl
  • R J - and R i ⁇ are independently hydrogen or methyl
  • R 13 for hydrogen, (C 1 -C 1Q ) alkyl, 2-methoxyethyl, phenyl, 3-phenylpropyl, 3-cyclohexylpropyl, (C ⁇ -C ⁇ ) alkanoyl, hydroxyacetyl, unsubstituted or substituted in the alkyl part by a phenyl radical Amino- (C2 ⁇ Cg) alkanoyl or ((C 1 -C2) alkoxy) carbonyl; A ⁇ represents a pharmacologically acceptable anion; and their tautomeric forms and their pharmacologically acceptable salts, but if X is oxygen and at the same time R is R -CH2-, min-
  • R 3 CHO
  • R 4 CH 2 OH
  • R J COMe
  • R 4 CH 2 0H
  • R 3 H D
  • R 3 CO- (2-chlorophenyl)
  • R 4 H
  • R 3 CO- (3-chlorophenyl)
  • R 4 H
  • R 3 CO- (4-chlorophenyl)
  • R 4 H
  • Example 91
  • R 3 CO- (2-chlorophenyl)
  • R 4 H
  • R 3 C0- (4-chlorophenyl)
  • R 4 H
  • R 3 CO- (3-fluorophenyl)
  • R 4 H
  • R 3 CO- (2,3,4-trimethoxyphenyl)
  • R 4 H
  • R 3 CO- (4-tert-butylphenyl)
  • R 4 H
  • R 3 COMe
  • R 4 4-acetylaminophenyl
  • the co-product L-citrulline which is produced when NO is formed by purified NOS, is recorded quantitatively.
  • J H-radiolabeled L-arginine is used as the substrate of the enzyme reaction, which is converted to J HL-citrulline and NO.
  • L-citrulline formed is removed from the reaction mixture by unused L-arginine by means of ion exchange chromatography; the 3 H activity measured by liquid scintillation then corresponds to the amount of L-citrulline, which is a direct measure of the activity of the NOS.
  • the basic medium for carrying out the enzyme reaction is TE buffer (triethanolamine, EDTA, pH 7.0).
  • the final volume of each incubation is 100 ⁇ l.
  • the reaction mixture is obtained by mixing the following 6 components on ice:
  • REA mix pH 7.0 containing triethanolamine, calcium chloride, magnesium chloride, EDTA, L-arginine, calmodulin and flavin adenine dinucleotide (FAD); 2. freshly prepared stock solution ' on ß-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH); 3. (6R) -5,6,7,8-tetrahydro-L-biopterin-dihydrochloride stock solution (BH 4 ) or - for experiments without BH 4 - instead TE ⁇ buffer; 4. purified NO synthase from pig cerebellum or from pig liver;
  • Substance 100 ⁇ M 100 ⁇ M. After mixing the components on ice, the reaction mixture is immediately incubated in a water bath at 37 ° C. for 15 minutes. After this incubation period, the reaction is stopped by adding 900 ⁇ l of ice-cold "stop buffer" (20 mM sodium acetate, 2 mM EDTA, pH 5.5) and the mixture (total volume now 1.0 ml) is placed on ice. To separate the unreacted 3 HL arginine, the mixture is placed on an ion exchanger column with 0.8 ml Dowex AG 50 WX-8 (100-200 esh), which had previously been rinsed with 2 ml stop buffer and equilibrated.
  • stop buffer 20 mM sodium acetate, 2 mM EDTA, pH 5.5
  • the column is eluted twice with 1 ml of water each time.
  • the passage of the sample and the eluate are collected in scintillation vials and cleaned (total volume 3 ml).
  • 9 ml of scintillator solution are added to the 3 ml of aqueous measurement solution and the homogeneous mixture is measured in a Tricarb 2500 TR (Packard) liquid scintillation counter for 1 minute per sample.
  • the activity found with the substance to be tested is given in percent of the activity of the control.
  • Each substance is tested in a concentration of 100 ⁇ M in the presence of 2 ⁇ M tetrahydrobiopterin for an antagonistic effect and in the absence of tetrahydrobioopterin for an agonistic effect on the NOS.
  • Tablets containing 40 mg of active ingredient per tablet 40 mg of active ingredient per tablet

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Abstract

L'invention concerne des dérivés de ptéridine de la formule générale (I), dans laquelle X désigne O ou NH et R4 désigne par ex. hydrogène, phényle ou le reste R4a-CH2-, et R4a désigne par ex. hydrogène, alkyl(C¿1?-C4)mercapto, le reste -NR?11R12¿ ou le reste -OR13, et dans laquelle, R?1, R2, R3, R5, R6, R7, R11, R12 et R13¿ correspondant à la notation mentionnée dans la revendication 1. Ces dérivés de ptéridine sont des inhibiteurs de la NO-synthase. L'invention concerne leur utilisation dans le traitement de maladies dues à une élévation du taux de monoxyde d'azote.
PCT/EP1995/001785 1994-05-24 1995-05-11 Utilisation de derives de tetrahydropteridine comme inhibiteurs de la no-synthase Ceased WO1995032203A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP95921745A EP0760818B1 (fr) 1994-05-24 1995-05-11 Utilisation de derives de tetrahydropteridine comme inhibiteurs de la no-synthase
JP53002295A JP4287506B2 (ja) 1994-05-24 1995-05-11 Ｎｏ−合成酵素阻害剤としてのテトラヒドロプテリジン誘導体の使用
DE59510094T DE59510094D1 (de) 1994-05-24 1995-05-11 Verwendung von tetrahydropteridin-derivaten als hemmstoffe der no-synthase
AT95921745T ATE214068T1 (de) 1994-05-24 1995-05-11 Verwendung von tetrahydropteridin-derivaten als hemmstoffe der no-synthase
CA002188267A CA2188267C (fr) 1994-05-24 1995-05-11 Utilisation de derives de tetrahydropteridine comme inhibiteurs de la no-synthase

Applications Claiming Priority (2)

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DEP4418097.7 1994-05-24
DE4418097A DE4418097A1 (de) 1994-05-24 1994-05-24 Verwendung von Tetrahydropteridin-Derivaten als Hemmstoffe der NO-Synthase

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US08750011 A-371-Of-International 1995-05-11
US09/357,212 Continuation US6858612B1 (en) 1994-05-24 1999-07-20 Use of tetrahydropteridine derivatives as no synthase inhibitors

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WO1995032203A2 true WO1995032203A2 (fr) 1995-11-30
WO1995032203A3 WO1995032203A3 (fr) 1995-12-28

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US (1) US6858612B1 (fr)
EP (1) EP0760818B1 (fr)
JP (1) JP4287506B2 (fr)
AT (1) ATE214068T1 (fr)
DE (2) DE4418097A1 (fr)
ES (1) ES2173185T3 (fr)
PT (1) PT760818E (fr)
WO (1) WO1995032203A2 (fr)

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US5854234A (en) * 1993-10-21 1998-12-29 G. D. Searle & Co. Amidino dervatives useful as nitric oxide synthase inhibitors
US5883251A (en) * 1995-04-20 1999-03-16 G. D. Searle & Co. Azepine derivatives useful as nitric oxide synthase inhibitors
US5945408A (en) * 1996-03-06 1999-08-31 G.D. Searle & Co. Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors
US5958958A (en) * 1997-07-22 1999-09-28 G.D. Searle & Co. 1,2,4-oxa diazolino and 1,24-oxa diazolidion heterocycles as useful nitric oxide synthase inhibitors
WO2000039129A1 (fr) * 1998-12-28 2000-07-06 K.U. Leuven Research & Development Effets immunosuppresseurs de derives de la pteridine
WO2000074678A1 (fr) * 1999-06-09 2000-12-14 Ono Pharmaceutical Co., Ltd. Analgesique
US6344473B1 (en) 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US6489323B1 (en) 1998-06-10 2002-12-03 G.D. Searle & Co. Heterobicyclic and tricyclic nitric oxide synthase inhibitors
WO2004084906A1 (fr) * 2003-03-25 2004-10-07 Vasopharm Biotech Gmbh Utilisation de derives de pteridine pour le traitement de pression intracranienne accrue, d'ischemie secondaire, et de troubles associes a un niveau accru d'especes reactives cytotoxiques de l'oxygene
US6844343B1 (en) 1999-09-17 2005-01-18 Vasopharm Biotech Gmbh N-substituted 4-aminopteridines, synthesis and use thereof as pharmaceutical agent
US6858612B1 (en) 1994-05-24 2005-02-22 Vasopharm Buitech Gmbh Use of tetrahydropteridine derivatives as no synthase inhibitors
EP0908182B2 (fr) † 1996-08-30 2007-03-28 Daiichi Asubio Pharma Co., Ltd. Preparations servant a la prevention et au traitement de maladies provoquees par une hypofonction de l'oxyde nitrique synthase
JP2007525407A (ja) * 2003-12-30 2007-09-06 ヴァソファーム バイオテック ゲーエムベーハー ４−アミノ−７，８−ジヒドロプテリジン類、これらを含む医薬組成物、および一酸化窒素レベル上昇によってもたらされる疾病の治療に対するそれらの使用
US7276506B2 (en) 1998-12-28 2007-10-02 4 Aza Bioscience Nv Immunosuppressive effects of pteridine derivatives
US10144736B2 (en) 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
US10285990B2 (en) 2015-03-04 2019-05-14 Gilead Sciences, Inc. Toll like receptor modulator compounds
US10370342B2 (en) 2016-09-02 2019-08-06 Gilead Sciences, Inc. Toll like receptor modulator compounds
US10640499B2 (en) 2016-09-02 2020-05-05 Gilead Sciences, Inc. Toll like receptor modulator compounds
US11286257B2 (en) 2019-06-28 2022-03-29 Gilead Sciences, Inc. Processes for preparing toll-like receptor modulator compounds
US11396509B2 (en) 2019-04-17 2022-07-26 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11583531B2 (en) 2019-04-17 2023-02-21 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US12049461B2 (en) 2006-07-20 2024-07-30 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections

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ES2186055T3 (es) * 1998-07-10 2003-05-01 Ernst Werner Fabricacion de un medio destinado a impedir el rechazo del transplante.
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US6046211A (en) * 1993-10-21 2000-04-04 G.D. Searle & Co. Amidino derivatives useful as nitric oxide synthase inhibitors
US5854234A (en) * 1993-10-21 1998-12-29 G. D. Searle & Co. Amidino dervatives useful as nitric oxide synthase inhibitors
US6448286B1 (en) 1993-10-21 2002-09-10 G.D. Searle & Co. Imino pyrrolidine derivatives useful as nitric oxide synthase inhibitors
US6071906A (en) * 1993-10-21 2000-06-06 G. D. Searle & Co. Imidino piperidine derivatives useful as nitric oxide synthase inhibitors
US6858612B1 (en) 1994-05-24 2005-02-22 Vasopharm Buitech Gmbh Use of tetrahydropteridine derivatives as no synthase inhibitors
US5883251A (en) * 1995-04-20 1999-03-16 G. D. Searle & Co. Azepine derivatives useful as nitric oxide synthase inhibitors
US6043261A (en) * 1995-04-20 2000-03-28 G. D. Searle & Co. Pyrrolodino imidines useful as nitric oxide synthase inhibitors
US5945408A (en) * 1996-03-06 1999-08-31 G.D. Searle & Co. Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors
JPH10338637A (ja) * 1996-08-30 1998-12-22 Yoshiharu Kanayama Ｎｏｓの機能低下が寄与する疾患の予防または治療剤
US7820667B2 (en) 1996-08-30 2010-10-26 Daiichi Sankyo Company, Limited Methods of treating hypertension
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US5981556A (en) * 1997-07-22 1999-11-09 G.D. Searle & Co. 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors
US6136829A (en) * 1997-07-22 2000-10-24 G.D. Searle & Co. Oxathiadiazole derivatives usful as iNOS inhibitors
US5958958A (en) * 1997-07-22 1999-09-28 G.D. Searle & Co. 1,2,4-oxa diazolino and 1,24-oxa diazolidion heterocycles as useful nitric oxide synthase inhibitors
US6489323B1 (en) 1998-06-10 2002-12-03 G.D. Searle & Co. Heterobicyclic and tricyclic nitric oxide synthase inhibitors
WO2000039129A1 (fr) * 1998-12-28 2000-07-06 K.U. Leuven Research & Development Effets immunosuppresseurs de derives de la pteridine
US7501513B2 (en) 1998-12-28 2009-03-10 4 Aza Bioscience Nv Immunosuppressive effects of pteridine derivatives
US7276506B2 (en) 1998-12-28 2007-10-02 4 Aza Bioscience Nv Immunosuppressive effects of pteridine derivatives
WO2000074678A1 (fr) * 1999-06-09 2000-12-14 Ono Pharmaceutical Co., Ltd. Analgesique
US6844343B1 (en) 1999-09-17 2005-01-18 Vasopharm Biotech Gmbh N-substituted 4-aminopteridines, synthesis and use thereof as pharmaceutical agent
US6344473B1 (en) 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US9382252B2 (en) 2003-03-25 2016-07-05 Vasopharm Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
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US8222238B2 (en) 2003-03-25 2012-07-17 Vasopharm Biotech Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
WO2004084906A1 (fr) * 2003-03-25 2004-10-07 Vasopharm Biotech Gmbh Utilisation de derives de pteridine pour le traitement de pression intracranienne accrue, d'ischemie secondaire, et de troubles associes a un niveau accru d'especes reactives cytotoxiques de l'oxygene
US9422289B2 (en) 2003-03-25 2016-08-23 Vasopharm Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
JP2007525407A (ja) * 2003-12-30 2007-09-06 ヴァソファーム バイオテック ゲーエムベーハー ４−アミノ−７，８−ジヒドロプテリジン類、これらを含む医薬組成物、および一酸化窒素レベル上昇によってもたらされる疾病の治療に対するそれらの使用
US7541360B2 (en) 2003-12-30 2009-06-02 Vasopharm Gmbh 4-amino-7,8-dihydropteridines, pharmaceutical compositions containing them and their use for the treatment of diseases which are caused by an increased nitric oxide level
US12049461B2 (en) 2006-07-20 2024-07-30 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections
US10144736B2 (en) 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
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US11827609B2 (en) 2016-09-02 2023-11-28 Gilead Sciences, Inc. Toll like receptor modulator compounds
US11124487B2 (en) 2016-09-02 2021-09-21 Gilead Sciences, Inc. Toll like receptor modulator compounds
US10640499B2 (en) 2016-09-02 2020-05-05 Gilead Sciences, Inc. Toll like receptor modulator compounds
US11396509B2 (en) 2019-04-17 2022-07-26 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11583531B2 (en) 2019-04-17 2023-02-21 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11286257B2 (en) 2019-06-28 2022-03-29 Gilead Sciences, Inc. Processes for preparing toll-like receptor modulator compounds

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PT760818E (pt) 2002-08-30
JP4287506B2 (ja) 2009-07-01
EP0760818A1 (fr) 1997-03-12
ATE214068T1 (de) 2002-03-15
ES2173185T3 (es) 2002-10-16
US6858612B1 (en) 2005-02-22
WO1995032203A3 (fr) 1995-12-28
DE4418097A1 (de) 1995-11-30
EP0760818B1 (fr) 2002-03-06
JPH10500417A (ja) 1998-01-13
DE59510094D1 (de) 2002-04-11

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